title: Heightened efficacy of nitric oxide-based therapies in type II diabetes mellitus and metabolic syndrome.
abstract: Type II diabetes mellitus (DM) and metabolic syndrome are associated with accelerated restenosis following vascular interventions due to neointimal hyperplasia. The efficacy of nitric oxide (NO)-based therapies is unknown in these environments. Therefore, the aim of this study is to examine the efficacy of NO in preventing neointimal hyperplasia in animal models of type II DM and metabolic syndrome and examine possible mechanisms for differences in outcomes. Aortic vascular smooth muscle cells (VSMC) were harvested from rodent models of type II DM (Zucker diabetic fatty), metabolic syndrome (obese Zucker), and their genetic control (lean Zucker). Interestingly, NO inhibited proliferation and induced G0/G1 cell cycle arrest to the greatest extent in VSMC from rodent models of metabolic syndrome and type II DM compared with controls. This heightened efficacy was associated with increased expression of cyclin-dependent kinase inhibitor p21, but not p27. Using the rat carotid artery injury model to assess the efficacy of NO in vivo, we found that the NO donor PROLI/NO inhibited neointimal hyperplasia to the greatest extent in type II DM rodents, followed by metabolic syndrome, then controls. Increased neointimal hyperplasia correlated with increased reactive oxygen species (ROS) production, as demonstrated by dihydroethidium staining, and NO inhibited this increase most in metabolic syndrome and DM. In conclusion, NO was surprisingly a more effective inhibitor of neointimal hyperplasia following arterial injury in type II DM and metabolic syndrome vs. control. This heightened efficacy may be secondary to greater inhibition of VSMC proliferation through cell cycle arrest and regulation of ROS expression, in addition to other possible unidentified mechanisms that deserve further exploration.
authors.affiliation: Division of Vascular Surgery, Institute for BioNanotechnology in Medicine, Northwestern University, 201 E. Huron St., Galter 10-105, Chicago, IL 60611, USA.
authors.forename: Sadaf S
authors.initials: SS
authors.lastname: Ahanchi
authors.forename: Vinit N
authors.initials: VN
authors.lastname: Varu
authors.forename: Nick D
authors.initials: ND
authors.lastname: Tsihlis
authors.forename: Janet
authors.initials: J
authors.lastname: Martinez
authors.forename: Charles G
authors.initials: CG
authors.lastname: Pearce
authors.forename: Muneera R
authors.initials: MR
authors.lastname: Kapadia
authors.forename: Qun
authors.initials: Q
authors.lastname: Jiang
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Saavedra
authors.forename: Larry K
authors.initials: LK
authors.lastname: Keefer
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hrabie
authors.forename: Melina R
authors.initials: MR
authors.lastname: Kibbe
mesh_terms: D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D020212:Carotid Artery Injuries / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004261:DNA Replication / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006965:Hyperplasia; D008297:Male; D024821:Metabolic Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D011392:Proline / Q000031:analogs & derivatives / Q000494:pharmacology; D051381:Rats; D011924:Rats, Zucker; D017382:Reactive Oxygen Species / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D014226:Triazenes / Q000494:pharmacology; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: C105351:1-hydroxy-2-oxo-3,3-bis(2-aminoethyl)-1-triazene; D020030:Nitric Oxide Donors; D017382:Reactive Oxygen Species; D014226:Triazenes; C102043:proline-nitric oxide; D009569:Nitric Oxide; C002744:3-nitrotyrosine; D014443:Tyrosine; D026423:S-Nitroso-N-Acetylpenicillamine; D011392:Proline